In previous work it was found that inorganic pyrophosphate (PP sub i) inhibits both formation and dissolution of hydroxyapatite crystals in vitro. PP sub i, which has long been known to be present in bone, has further been detected in teeth, saliva, urine and blood. In the latter, elevated levels of PP sub i were found in three diseases of failure of calcification, i.e. hypophosphatasia, osteomalacia and renal failure. Thus it is possible that this compound could have a physiological role in the process of calcification. Compounds related to PP sub i, but containing a P-C-P bond instead of a P-O-P bond, have been found to have similar effects in vitro. These substances, called diphosphonates, are not broken down in the body. When administered to animals and man, they inhibit both ectopic calcification induced by various means and bone resorption. Certain diphosphonates also inhibit bone mineralization. It is now planned to investigate: 1. PP sub i and alkaline, neutral and acid pyrophosphatase at the site of cartilage calcification. 2. The handling and metabolism of PP sub i by various cell types. 3. PP sub i in plasma in various types of osteomalacia and rickets. 4. The possible action of diphosphonates at the cellular level. 5. The diphosphonates as a tool to study the regulation of calcium homeostasis and vitamin D metabolism.